Melanin is a complex biopolymer that is synthesized in organelles called melanosomes that are a unique feature of melanocytes. Melanocytes are cells that reside in the basal layer of the epidermis and transfer melanin to neighboring keratinocytes. In melanin synthesis, early oxidative steps in which phenolic and catecholic precursors are oxidized to orthoquinones occurs. Regulation of melanin production occurs at multiple points that primarily involve, but are not exclusive to, the regulation of tyrosinase, which is the key enzyme in melanin synthesis (Wang et al., “Tyrosinase Maturation Through the Mammalian Secretory Pathway: Bringing Color to Life,” Pigment Cell Res. 19:3-18 (2006); Wang et al., “Regulation of Tyrosinase Trafficking and Processing by Presenilins: Partial Loss of Function by Familial Alzheimer's Disease Mutation,” Proc. Natl. Acad. Sci. USA 103:353-8 (2006)). However, because over 100 genes are implicated in control of pigmentation, other regulatory targets are likely to exist.
Melanin is important for disease prevention, because it absorbs ultraviolet light in the UVB and UVA spectrum. This protects keratinocytes from the mutagenic effects of sunlight. In addition, melanin has a social function, because it determines skin and hair color. Cutaneous cancers such as squamous cell carcinoma and basal cell carcinoma are directly linked to exposure to ultraviolet irradiation, and it is widely accepted that people with light skin are at much higher risk to develop skin cancer due to a comparative lack of melanin compared with dark skinned individuals (Gallagher et al., “Adverse Effects of Ultraviolet Radiation: A Brief Review,” Prog. Biophys. Mol. Biol. 92(1):119-31 (2006)).
Agents that increase melanin synthesis are of interest, because of their potential use as “natural sunscreens” that stimulate the skin's resident melanocytes to produce and transfer more melanin to epidermal keratinocytes, thus decreasing the incidence of skin cancer. There is a significant need to identify new compounds with improved ability to induce melanin production and transfer. The development of libraries of compounds that can be rapidly screened for their ability to modulate melanin production would facilitate drug discovery that could have a profound impact on the incidence of skin cancer.
The present invention is directed to overcoming these and other deficiencies in the art.